Elicitation of antibodies against targets that are immunorecessive, cryptic, or transient in their native context is a challenge for vaccine design. One potential solution is precise immunogen design. The ability of structural biology to provide atomic-level definition of antibody-antigen interactions and of computational biology to manipulate protein structure has raised the possibility at least for protein antigens of precisely replicating the antigenic surface recognized by a target antibody. Recent successes in immunogen design by transplanting an epitope to foreign scaffolds and in focusing the antibody response to a precise site using computational techniques, termed scaffolding/epitope-transplantation and antigenic resurfacing, respectively highlight the notion that computational biology may play a crucial role in vaccine design. Rather than relying on a small set of well-defined tools, however, increasing evidence suggests that vaccine design will require the systematic development of computational algorithms, methods, and tools associated with the analysis, design, of manipulation of protein structures and protein-protein (or protein-ligand) interactions. Here we address a number of technological issues that are expected to impact structure-based vaccine design. Specifically, we describe the development of new protein design and structure-modeling algorithms, methods, and tools that are particularly suited for vaccine design.